a. Field of Invention
This invention relates to derivatives of the tetradecapeptide somatostatin. More particularly, this invention concerns peptide derivatives of retro-enantio-somatostatin and salts thereof, a process for preparing the peptide derivatives and salts, intermediates used in the process and methods for using the peptide derivatives and their salts.
b. Prior Art
The name "somatostatin" has been proposed for the factor found in hypothalamic extracts which inhibits the secretion of growth hormone (somatotropin). The structure of this factor has been elucidated by P. Brazeau, et al., Science, 179, 77 (1973) and reported to be the following tetradecapeptide structure: ##STR9##
The abbreviations used herein for the various amino acids are Ala, alanine; Asn, asparagine; Cys, cysteine; Gly, glycine; Lys, lysine; Phe, phenylalanine; Ser, serine; Thr, threonine; and Trp, tryptophane.
The constitution of the tetradecapeptide somatostatin has been confirmed by synthesis; for example, see D. Sarantakis and W. A. McKinley, Biochem. Biophys. Res. Comm., 54, 234 (1973), J. Rivier, et al., Compt. Rend. Ser. D, 276, 2737 (1973) and H.U. Immer et al., Helv. Chim. Acta, 57, 730 (1974).
The important physiological activity of this tetradecapeptide established it as a compound of significance for clinical pharmacology relating to the treatment of acromegaly and the management of diabetes; for example, see K. Lundbaek, et al., Lancet, 2, 131 (1970) and R. Guillemin in "Chemistry and Biology of Peptides" J. Meienhofer, Ed., 3rd American Peptide Symposium Boston 1972, Ann Arbor Science Publications, Ann Arbor, Mich., 1972, pp 585 -600.
The linear form of somatostatin, having two sulfhydryl groups instead of a disulfide bridge, has been prepared recently by J.W.F. Rivier, J. Amer. Chem. Soc., 96, 2986 (1974). He reports that the linear form is equipotent to somatostatin based on the ability of the two compounds to inhibit the rate of secretion of growth hormone by rat pituitary cells in monolayer tissue cultures.
Only recently have there been reported polypeptides, other than the natural hormone and its linear form, having somatostatin-like activity. D. Sarantakis, et al., Biochem. Biophys. Res. Comm., 55, 538 (1973) reported the synthesis of the somatostatin analog, [Ala.sup.3,14 ]-somatostatin, by solid phase methods. This analog exhibited a very small amount of activity, about 0.01% of somatostatin's potency. P. Brazeau, et al., Biochem. Biophys. Res. Comm., 60, 1202 (1974) recently reported the synthesis of a number of acylated des[Ala.sup.1 -Gly.sup.2 ]-somatostatin compounds, by solid phase methods.
The present invention discloses new analogs of somatostatin based on the principle of the retro-enantio system. This system is achieved by construction of a reversed sequence of amino acids having opposite configuration, i.e., D instead of L, to give the "retro-enantio" isomer of the natural peptide. It is surprising that the retro-enantio derivatives of somatostatin of formulae I or Ia have been found to retain the activity of the natural hormone somatostatin notwithstanding the fact that other hormones of the retro-enantio system have shown a range of retention of full activity to complete loss of activity, as reported in the review by J. Rudinger, The Design of Peptide Hormone Analogs, pp 368 -369 in Drug Design, Vol. II, Ed. E.J. Ariens, Academic Press, New York and London, 1971.
The present invention discloses retro-enantio peptide derivatives which retain the activity of the natural hormone somatostatin. The derivatives are prepared readily by a convenient process, which includes the following advantages: the process starts from readily available materials, avoids noxious reagents, is executed facilely and utilizes easily removable protecting groups.
The foregoing advantages and attributes render the peptides of this invention useful for the management of diabetes and the treatment of acromegaly.